Patent GB-1535602-A (GB)
Title: Lhrh peptide derivatives
IPC: A61K38/00
Filed: 1976-06-11
Abstract: 1535602 LHRH peptides ADMINISTRATORS OF THE TULANE UNIVERSITY EDUCATIONAL FUND 11 June 1976 [12 June 1975 (2) 27 Jan 1976] 24273/76 Heading C3H Peptides of Formula (I) wherein (i) X is Ser, Y is D-Trp, Z is Gly-NH 2 ; or (ii) X is Ser, Y is D-Phe, Z is Gly-NH 2 ; or (iii) X is D-Ser, Y is D-Leu, Z is NHR<SP>1</SP> wherein R<SP>1</SP> is C 1 -C 3  alkyl; and the non-toxic, pharmaceutically-acceptable salts thereof. The salt may be an acid addition salt, preferably of acetic acid, lactic acid, succinic acid, benzoic acid, salicylic acid, methanesulphonic acid, p - toluenesulphonic acid, hydrochloric acid, phosphoric acid, tannic acid or carboxymethylcellulose. Peptides of Formula (II) wherein (i) X<SP>1</SP> is Ser(R<SP>6</SP>), Y is D-Trp, Z<SP>1</SP> is Gly-R<SP>2</SP>; or (ii) X<SP>1</SP> is Ser(R<SP>6</SP>), Y is D-Phe, Z<SP>1</SP> is Gly-R<SP>2</SP>; or (iii) X<SP>1</SP> is D-Ser(R<SP>6</SP>), Y is D-Leu, Z<SP>1</SP> is OR<SP>3</SP> wherein R<SP>2</SP> is amino or O(C 1 -C 3  alkyl), R<SP>3</SP> is C 1 -C 3  alkyl, R<SP>4</SP>, R<SP>5</SP>, R<SP>6</SP>, R<SP>7</SP> are protective groups which may be eliminated without affecting the compounds of Formula (I), R<SP>8</SP> is hydrogen or one of said protective groups. Peptides of Formula (III) R<SP>8</SP>-Pyroglu-His-Trp-D-Ser(R<SP>6</SP>)-Tyr(R<SP>5</SP>)-D-Leu- Leu-Arg(R<SP>4</SP>)-Pro-NHR<SP>1</SP> wherein R<SP>1</SP> is C 1 -C 3  alkyl. Peptides of Formula (IV) R<SP>8</SP>-Pyroglu-His(R<SP>7</SP>)-Trp-X<SP>1</SP>-Tyr(R<SP>5</SP>)-Y-Leu- Arg(R<SP>4</SP>)-Pro-Z<SP>2</SP> wherein (i) X<SP>1</SP> is Ser(R<SP>6</SP>), Y is D-Trp, Z<SP>2</SP> is Gly-A; or (ii) X<SP>1</SP> is Ser(R<SP>6</SP>), Y is D-Phe, Z<SP>2</SP> is Gly-A; or (iii) X<SP>1</SP> is D-Ser(R<SP>6</SP>), Y is D-Leu, Z<SP>2</SP> is A<SP>1</SP> wherein A is A<SP>1</SP> is (Formula II as shown above) wherein # is phenyl and #<SP>1</SP> is phenylene, R<SP>4</SP> is preferably tosyl, nitro, benzyloxycarbonyl or adamantyloxycarbonyl wherein, if R<SP>4</SP> is nitro or tosyl, protection is on one of the N<SP>#</SP>,N<SP>#1</SP>nitrogen atoms and, if R<SP>4</SP> is benzyloxycarbonyl or adamantyloxycarbonyl, protection is on the N nitrogen atom and one of the N<SP>#</SP>,N<SP>#1</SP>- nitrogen atoms; R<SP>5</SP> is preferably benzyl, 2. bromobenzyloxycarbonyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4- dichlorobenzyl or benzyloxycarbonyl; R<SP>7</SP> is preferably tosyl or 2,4-dinitrophenyl; R<SP>8</SP> is preferably t-butyloxycarbonyl, benzyloxycarbonyl, t-amyloxycarbonyl, cyclopentyloxycarbonyl or isobornyloxycarbonyl; R<SP>6</SP> is preferably benzyl, 2-bromobenzyloxycarbonyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, 2,4-dichlorobenzyl, trityl or benzyloxycarbonyl. The peptides may be prepared by solid phase synthesis, preferably using chloromethylated, hydroxymethyl or benzhydrylamine resin. In the examples peptides prepared are: H - Pyroglu - His - Trp - Ser - Tyr - D - Trp- Leu - Arg - Pro - Gly - NH 2 ; H - Pyroglu - His- Trp - Ser - Tyr - D - Phe - Leu - Arg - Pro - Gly- NH 2 ; H - Pyroglu - His - Trp - D - Ser - DLeu - Leu - Arg - Pro - NHC 2 H 5 ; H - Pyroglu- His(Tos) - Ser(Bzl) - Tyr(2BrCbz) - D - Trp- Leu - Arg(Tos) - Pro - Gly - benzhydrylamine resin; H - Pyroglu - His(Tos) - Ser(Bzl) - Tyr- (2BrCbz) - D - Phe - Leu - Arg(Tos) - Pro - Glybenzhydrylamine resin; H - Pyroglu - His- (Dnp) - Trp - D - Ser(Bzl) - Tyr(2BrCbz) - DLeu - Leu - Arg(Tos) - Pro - OCH2 - resin support; H - Pyroglu - His - Trp - D - Ser(Bzl)- Tyr(2BrCbz) - D - Leu - Leu - Arg(Tos) - Pro- NHC 2 H 5 . Pharmaceutical compositions, which may be used to inhibit fertility in female mammals, preferably in unit doage form, comprise peptides (I), or a pharmaceutically-acceptable, non-toxic salt thereof, in admixture with a pharmaceutically-acceptable carrier.